696 
PHARMACOLOGY 
Table V. — The Dose of Amphetamine Injected I.V., the 
Biological Half-life of the Drug and the Cumulative 
Amounts of Amphetamine Excreted in Urine and Bile 
of Dogs 
Total Urine pH Cumulative amount of 
Subject dose mean value ti/: amphetamine (4 hr) 
doK (mg) (range) <hr) Urine (mg) Bile (j^f;) 
R 13 7.50 6.13 1.25 3.79 
(7.38-7.76) 
T 10 5.96 3.67 2.10 5.00* 
(5.92-6.00) 
V 10 6.56 4.25 1.77 5.50 
(6.48-6.61) 
X _ 10 6.51 4.18 1.80 6.87 
(6.48-6.54) 
Z .._ 13 6.28 3.85 3.25 6.60 
(6.20-6.38) 
• = 3 hours 
The plasma amphetamine concentration ver- 
sus time profiles in intact and nephrectomized 
dogs are shown in Figure 4. The biological 
half -life was extended by almost 25 % following 
nephrectomy and the difference between the 
mean half-lives in intact and nephrectomized 
dogs was statistically very highly significant 
(Student's "t"-test, p<0.001). Nephrectomy 
did not significantly change the corrected ap- 
parent specific volume of distribution of this 
drug. The extent of protein binding (mean ± 
S.E.) in tact (23.1% ± 1.7) and nephrecto- 
mized (24.3% ± 1.5) dogs was not significantly 
different (Student's "t"-test, p>0.05). It thus 
appears that uremia had no effect upon the ex- 
tent of plasma protein binding of amphetamine. 
Desmethylimipramine had almost normal bind- 
ing in plasmas from uremic patients while the 
extent of binding of diphenylhydantoin was 
reduced.32 The extents of protein binding in the 
dog determined by the in vitro equilibrium di- 
alysis technique and by measuring in vivo the 
amphetamine concentrations in plasma and cer- 
ebrospinal fluid collected simultaneously were 
not significantly different (Student's "t"- test, 
p>0.05, Table VII). 
SUMMARY 
A relationship appeared to exist between die- 
tary habit of the various species of animals and 
the following observations. 
1. Biological Half-life of the Drug. The half- 
life was significantly longer in carnivorous 
species (dog and cat) than in herbivorous 
(pony, rabbit and goat) and omnivorous 
(swine, rat^^ and chicken) species, except 
man.^'^ 
2. Metabolic Pattern.^'^ Herbivorous species 
metabolized the phenylisopropylamine 
group largely by oxidative deamination. 
Carnivorous and omnivorous species uti- 
lized aromatic hydroxylation as well as ox- 
idative deamination. 
Some similarities were observed in the fate of 
amphetamine among the several species of ani- 
mals. The rapid attainment of distribution equi- 
librium, low extent of plasma protein binding 
and large apparent volume of distribution were 
characteristics of this drug in all species. While 
the proportion of dose excreted unchanged in 
urine varied considerably among species, biliary 
Table VI. — Percent Dose (Mean — S.E.) of Amphetamine and of Its Metabolites in 24-Hour Urine of Different 
Species 
Species 
( number ) 
Urinary 
pH reaction Amphetamine 4-Hydroxy- 
(range) amphetamine 
Conjugates 
Percent dose ! 
recovered 
Goat (10) — 
Swine (6) . 
Pony (4) . 
Rabbit (9) . 
Chicken (4) 
Dog (6) 
Cat (8)* 
7.60 
(6.07-8.40) 
6.85 
(6.26-8.50) 
8.06 
(7.70-8.32) 
8.00 
(7.56-8.49) 
6.56 
(6.23-6.92) 
7.45 
(6.65-7.75) 
7.35 
(6.46-8.00) 
12 (1.5) 
15 (1.5) 
2 
3 (0.4) 
32 (3.8) 
30 (1.2) 
35 (2.2) 
11 (1.0) 
20 (2.5) 
12 
10 (0.9) 
7 (1.0) 
11 (2.2) 
5 (0.3) 
13 (2.3) 
27 (3.1) 
13 
8 (0.08) 
7 (2.2) 
4 (0.6) 
9 (0.8) 
21 (2.0) 
3 (0.4) 
6 
6 (0.4) 
12 (1.0) 
3 (0.4) 
10 (0.4) 
57 
66 
33 
27 
58 
48 
59 
• 48-hour urine 
